The present application relates to uk (GB) patent application number 1908219.7 filed on 10, 6, 2019, the contents of which are incorporated herein by reference in their entirety.
Detailed Description
Compounds of formula (I)
The present invention relates to a compound as described herein which is [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester (also referred to herein as "AX-8" or "Gly-O-iPr", shown below) or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in a method of treatment of the human or animal body by therapy, more particularly for use in a method of treatment of Chronic Cough (CC), including for example Refractory Chronic Cough (RCC) and Idiopathic Chronic Cough (ICC), and as described herein.
The compounds are structurally related to (-) -menthol and have the same chiral center of the same configuration as found in (-) -menthol.
In terms of structure, the compound may conveniently be described as the isopropyl ester of glycine amide corresponding to the carboxylic acid of (-) -menthol.
It may also be conveniently described as p-menthane carboxamide.
In one embodiment, the compound is [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof.
In one embodiment, the compound is [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound is [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester.
Use of the same
The compounds [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester (also referred to herein as "AX-8" or "Gly-O-iPr") as described herein may be used, for example, in the treatment of Chronic Cough (CC), including, for example, refractory Chronic Cough (RCC) and Idiopathic Chronic Cough (ICC), and as described herein.
Use in a method of treatment
One aspect of the present invention relates to a compound as described herein which is [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester (also referred to herein as "AX-8" or "Gly-O-iPr") or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in a method of treatment of the human or animal body by therapy, more particularly for use in a method of treatment of Chronic Cough (CC), including for example Refractory Chronic Cough (RCC) and Idiopathic Chronic Cough (ICC), and as described herein.
One aspect of the invention relates to a compound as described herein that is [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester (also referred to herein as "AX-8" or "Gly-O-iPr") or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with one or more (e.g., 1,2,3, 4) additional therapeutic agents as described herein, for use in a method of treating the human or animal body by therapy, more particularly for use in a method of treating Chronic Cough (CC), including, for example, refractory Chronic Cough (RCC) and Idiopathic Chronic Cough (ICC), and as described herein.
Use in the manufacture of a medicament
One aspect of the present invention relates to the use of the compound [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester (also referred to herein as "AX-8" or "Gly-O-iPr") or a pharmaceutically acceptable salt, hydrate or solvate thereof, as described herein, in the manufacture of a medicament for use in therapy, more particularly in the treatment of Chronic Cough (CC), including, for example, refractory Chronic Cough (RCC) and Idiopathic Chronic Cough (ICC), and as described herein.
In one embodiment, the medicament comprises the compound.
One aspect of the present invention relates to the use of the compound [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester (also referred to herein as "AX-8" or "Gly-O-iPr") or a pharmaceutically acceptable salt, hydrate or solvate thereof as described herein and one or more (e.g., 1, 2, 3, 4) additional therapeutic agents as described herein in the manufacture of a medicament for use in the treatment, more particularly in the treatment of Chronic Cough (CC), including, for example, refractory Chronic Cough (RCC) and Idiopathic Chronic Cough (ICC), and as described herein.
In one embodiment, the medicament comprises the compound and one or more (e.g., 1,2,3, 4) additional therapeutic agents.
Therapeutic method
One aspect of the present invention relates to a method of treatment, more particularly, a method of treatment of Chronic Cough (CC), including, for example, refractory Chronic Cough (RCC) and Idiopathic Chronic Cough (ICC), and as described herein, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound as described herein, which is [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester (also referred to herein as "AX-8" or "Gly-O-iPr") or a pharmaceutically acceptable salt, hydrate or solvate thereof, preferably in the form of a pharmaceutical composition.
One aspect of the present invention relates to a method of treatment, more particularly, a method of treatment of Chronic Cough (CC), including, for example, refractory Chronic Cough (RCC) and Idiopathic Chronic Cough (ICC), and as described herein, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound as described herein that is [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester (also referred to herein as "AX-8" or "Gly-O-iPr") or a pharmaceutically acceptable salt, hydrate or solvate thereof, preferably in the form of a pharmaceutical composition, and one or more (e.g., 1,2, 3, 4) additional therapeutic agents as described herein, preferably in the form of a pharmaceutical composition.
Medicine box
Another aspect of the invention relates to a kit comprising (a) a compound as described herein that is [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester (also referred to herein as "AX-8" or "Gly-O-iPr"), or a pharmaceutically acceptable salt, hydrate or solvate thereof, preferably as a pharmaceutical composition and provided in a suitable container and/or with a suitable package, and (b) instructions for its use, e.g., as to how to administer the compound to treat Chronic Cough (CC), including, e.g., refractory Chronic Cough (RCC) and idiopathic written chronic cough (ICC), and as described herein.
In one embodiment, the kit further comprises one or more (e.g., 1,2, 3, 4) additional therapeutic agents, as described herein.
The written instructions may also include a listing of specific indications for which the compound is suitable.
Chronic cough
As used herein, the term "chronic cough" (CC) refers to a cough that is sustained by an adult for more than about 8 weeks, or by a child for more than about 4 weeks.
Chronic cough is generally considered a symptom of the associated disorder.
In some cases, a related condition that may lead to a chronic cough (i.e., a well-defined chronic cough) may be identified. Common causes of chronic cough are, for example, asthma, eosinophilic bronchitis, postnasal drip syndrome (PNDS), gastroesophageal reflux disease (GORD), bronchodilation Chronic Obstructive Pulmonary Disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF).
In other cases, the relevant condition (i.e., unknown cause or idiopathic chronic cough) cannot be identified.
In some cases, the relevant condition may be identified and treated, and chronic cough ameliorated after treatment of the relevant condition.
In other cases, related conditions that may lead to chronic cough may be identified and treated, but chronic cough persists despite treatment of the related conditions. Here, persistent chronic cough may be considered as a refractory chronic cough (i.e., refractory to treatment of the relevant condition) or a idiopathic chronic cough (i.e., the cause remains unexplained). Such persistent chronic cough, whether described as idiopathic chronic cough or intractable chronic cough, can be considered a condition itself, not just a symptom.
Thus, chronic cough-specific therapies are useful for ameliorating a condition in a patient suffering from chronic cough, a condition not identified (idiopathic chronic cough), a condition identified as associated that results in chronic cough but is not treatable, a condition associated with treatable chronic cough, but associated with chronic cough that is refractory to treatment of the associated condition (refractory chronic cough).
In many cases, idiopathic/refractory chronic cough has a recognizable origin or history, e.g., an early stage condition symptomatic of chronic cough, which, despite treatment, causes persistent chronic cough. Such persistent chronic cough is often unrelated to early stage illness, but is often associated with changes in the nervous system that occur concurrently with or subsequent to early stage treatment.
For example, consider two patients with chronic cough as symptoms. Both are correctly diagnosed as asthma (related illness). Both are treated for asthma (related disorders). For both patients, most asthma symptoms were ameliorated. However, chronic cough was ameliorated for the first patient, but not for the second patient. This second patient, which was originally thought to explain chronic cough (due to asthma), is now diagnosed with refractory chronic cough (because it is refractory to the treatment of asthma, a related disorder) or idiopathic chronic cough (because the related disorder that now leads to persistent chronic cough is unknown, or unclear).
In one embodiment, the treatment is the treatment of chronic cough.
In one embodiment, the chronic cough is a well-defined chronic cough.
In one embodiment, the chronic cough is a symptom of, associated with, or caused by a diagnostic disorder.
In one embodiment, the chronic cough is a symptom of, associated with, or caused by a cough related disorder as a diagnosis.
In one embodiment, the chronic cough is a chronic cough associated with or caused by asthma, eosinophilic bronchitis, post-nasal drip syndrome (PNDS), gastroesophageal reflux disease (GORD), bronchodilation Chronic Obstructive Pulmonary Disease (COPD) or Idiopathic Pulmonary Fibrosis (IPF).
In one embodiment, the chronic cough is Idiopathic Chronic Cough (ICC).
In one embodiment, the chronic cough is a Refractory Chronic Cough (RCC).
In one embodiment, the chronic cough is a Refractory Chronic Cough (RCC) that persists, for example, following assessment and treatment of cough-related conditions according to accepted guidelines.
In one embodiment, the chronic cough is a Refractory Chronic Cough (RCC) that persists, for example, following assessment and treatment according to accepted guidelines, asthma, eosinophilic bronchitis, post-nasal drip syndrome (PNDS), gastroesophageal reflux disease (GORD), bronchodilation Chronic Obstructive Pulmonary Disease (COPD), or Idiopathic Pulmonary Fibrosis (IPF).
In one embodiment, chronic cough (including, for example, idiopathic chronic cough and refractory chronic cough) is a symptom of, associated with, or caused by allotussia.
In one embodiment, chronic cough (including, for example, idiopathic chronic cough and refractory chronic cough) is a symptom of, associated with, or caused by hypertussia.
In one embodiment, the chronic cough (including, for example, idiopathic chronic cough and refractory chronic cough) is, is associated with, or is caused by a symptom of the Cough Hypersensitivity Syndrome (CHS).
In one embodiment, chronic cough (including, for example, idiopathic chronic cough and refractory chronic cough) is, is associated with, or is caused by symptoms of Cough Hypersensitivity Reflex (CHR).
In one embodiment, chronic cough (including, for example, idiopathic chronic cough and refractory chronic cough) is a symptom of, associated with, or caused by laryngeal paresthesia.
In one embodiment, the chronic cough (including, for example, idiopathic chronic cough and refractory chronic cough) is, is associated with, or is caused by a symptom of the Laryngeal Hypersensitivity Syndrome (LHS).
In one embodiment, the chronic cough (including, for example, idiopathic chronic cough and refractory chronic cough) is a sensory neuropathic cough.
In one embodiment, chronic cough (including, for example, idiopathic chronic cough and refractory chronic cough) is a symptom associated with, or caused by, peripheral sensitization, central sensitization (cough central), and/or cortical and/or subcortical maladaptive plasticity.
In one embodiment, the chronic cough (including, for example, idiopathic chronic cough and refractory chronic cough) is, is associated with, or is caused by a symptom of vagal neuropathy.
In one embodiment, chronic cough (including, for example, idiopathic chronic cough and refractory chronic cough) is a symptom of, associated with, or caused by airway inflammation.
In one embodiment, the chronic cough (including, for example, idiopathic chronic cough and refractory chronic cough) is, is associated with, or is caused by neurogenic inflammation and/or symptoms of neuroinflammatory conditions.
Treatment of
The term "treatment" as used herein in the context of treating a disorder generally relates to treatment and therapy, whether human or animal (e.g., in veterinary applications), wherein some desired therapeutic effect is obtained, e.g., inhibiting the progression of the disorder, and includes reducing the rate of progression, terminating the rate of progression, alleviating symptoms of the disorder, ameliorating the disorder, and curing the disorder. Also included are treatments (i.e., prophylaxis) as a prophylactic measure. For example, the term "treatment" encompasses use with a patient who has not yet developed a condition but is at risk of developing a condition.
For example, treatment of chronic cough (including, for example, treatment of refractory chronic cough) includes preventing the cough, reducing the incidence of the cough (e.g., a shortness of breath cough), reducing the frequency of the cough (e.g., a frequency of the cough), reducing the severity of the cough (e.g., a severity of the cough), alleviating symptoms of the cough (e.g., alleviating throat irritation), and the like.
In one embodiment, the treatment is a reduction in one or more or all of cough frequency, cough severity, breathlessness cough, and throat irritation.
In one embodiment, the treatment is to reduce the frequency of cough.
In one embodiment, the treatment is to reduce the frequency of cough per hour.
In one embodiment, the treatment is to reduce the median cough frequency per hour.
In one embodiment, the treatment is to reduce the average cough frequency per hour.
In one embodiment, the treatment is to reduce the frequency of cough per hour of wakefulness.
In one embodiment, the treatment is to reduce the median awake cough frequency per hour.
In one embodiment, the treatment is to reduce the average hourly cough frequency of wakefulness.
In one embodiment, the treatment is to reduce the frequency of cough per hour of sleep.
In one embodiment, the treatment is to reduce the median hourly cough frequency in sleep.
In one embodiment, the treatment is to reduce the average hourly cough frequency of sleep.
In one embodiment, the treatment is to reduce the degree of cough delay.
In one embodiment, the treatment is to reduce acute cough.
In one embodiment, the treatment is a reduction in throat irritation.
In one embodiment, the treatment reduces cough frequency.
In one embodiment, the treatment reduces the frequency of cough per hour.
In one embodiment, the treatment reduces median cough frequency per hour.
In one embodiment, the treatment reduces the average cough frequency per hour.
In one embodiment, the treatment reduces the frequency of cough per hour of wakefulness.
In one embodiment, the treatment reduces the median awake cough frequency per hour.
In one embodiment, the treatment reduces the average hourly cough frequency of wakefulness.
In one embodiment, the treatment reduces the frequency of cough per hour of sleep.
In one embodiment, the treatment reduces the median hourly cough frequency in sleep.
In one embodiment, the treatment reduces the average hourly cough frequency of sleep.
In one embodiment, the treatment reduces the severity of cough.
In one embodiment, the treatment reduces acute cough.
In one embodiment, the treatment reduces throat irritation.
The term "therapeutically effective amount" as used herein relates to the amount of a compound, or a material, composition or dosage form comprising a compound, that is effective to produce some desired therapeutic effect commensurate with a reasonable benefit/risk ratio when administered according to a desired therapeutic regimen.
Route of administration
The compound [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester (also referred to herein as "AX-8" or "Gly-O-iPr") or a pharmaceutical composition comprising the compound as described herein may be administered to a subject by any convenient route of administration, whether systemic/peripheral or topical (i.e., at the desired site of action).
In a preferred embodiment, the route of administration is topical.
Routes of administration include oral (e.g., by ingestion), buccal mucosa, buccal (e.g., between the gums and cheeks), sublingual (e.g., under the tongue), transdermal (including, e.g., by patches, plasters, etc.), transmucosal (including, e.g., by patches, plasters, etc.), intranasal (e.g., by nasal spray, drops, or from a nebulizer or dry powder delivery device), pulmonary (e.g., by inhalation or insufflation therapy using, e.g., aerosols, e.g., by mouth or nose).
In a preferred embodiment, the route of administration is oral.
In a preferred embodiment, the route of administration is topical oral.
In a preferred embodiment, the route of administration is oral mucosa.
In a preferred embodiment, the route of administration is topical oral mucosa.
In a preferred embodiment, the route of administration is buccal.
In a preferred embodiment, the route of administration is topical buccal.
In a preferred embodiment, the route of administration is sublingual.
In a preferred embodiment, the route of administration is topical sublingual.
In a preferred embodiment, the route of administration is intranasal.
In a preferred embodiment, the route of administration is topical intranasal.
In a preferred embodiment, the route of administration is transmucosal.
In a preferred embodiment, the route of administration is topical transmucosal.
Dosage of
Those of skill in the art will appreciate that the appropriate dosage of the compound [ ((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester (also referred to herein as "AX-8" or "Gly-O-iPr") or composition comprising the compound as described herein may vary from patient to patient. Determining the optimal dose will generally involve balancing the level of therapeutic benefit against any risk or adverse side effects. The selected dosage level will depend on a variety of factors including the activity of the compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds and/or materials used in combination, the severity of the condition, as well as the type, sex, age, weight, condition, general health and prior medical history of the patient. The amount of the compound and the route of administration will ultimately be at the discretion of the physician, veterinarian or clinician, but generally the dosage will be chosen to achieve the desired effect at the site of action without causing generally deleterious or toxic side effects.
Administration may be achieved in one dose, continuously or intermittently (e.g., in divided doses at appropriate time intervals) throughout the course of treatment. Methods of determining the most effective mode and dosage of administration are well known to those skilled in the art and will vary with the formulation used for the treatment, the purpose of the treatment, the target cells being treated, and the subject being treated. Single or multiple administrations may be carried out according to the dosage level and pattern selected by the treating physician, veterinarian or clinician.
In one embodiment, the dosage is in the range of about 1 μg to about 5mg of compound per kilogram of subject body weight per day.
In one embodiment, the dosage is in the range of about 5 μg to about 2mg of compound per kilogram of subject body weight per day.
In one embodiment, the dosage is in the range of about 15 μg to about 0.7mg of compound per kilogram of subject body weight per day.
In one embodiment, the dosage is in the range of about 30 μg to about 0.4mg of compound per kilogram of subject body weight per day.
In one embodiment, the dosage is in the range of about 70 μg to about 0.3mg of compound per kilogram of subject body weight per day.
Similarly, in one embodiment, the dosage is in the range of about 0.07mg to about 350mg of the compound per day.
In one embodiment, the dosage is in the range of about 0.35mg to about 140mg of the compound per day.
In one embodiment, the dosage is in the range of about 1mg to about 50mg of the compound per day.
In one embodiment, the dosage is in the range of about 2mg to about 30mg of the compound per day.
In one embodiment, the dosage is in the range of about 5mg to about 20mg of the compound per day.
When the compound is a salt, ester, amide, prodrug, or the like, the amount applied is calculated based on the parent compound, and thus the actual weight to be used increases proportionally.
Treatment regimen
The compound or pharmaceutical composition comprising the compound may be administered according to any suitable treatment plan or regimen.
Most likely, administration will be "on demand" by the patient, according to the needs of the patient. For example, the patient may be instructed to self-administer the compound or a pharmaceutical composition comprising the compound at the time of the intended cough (e.g., as a precaution), immediately after the onset of the cough, after a prolonged period of cough, and the like.
As described herein, a single administration of 5mg ODT was found to have efficacy for up to about 8 hours, and thus it is expected that 2 to 4 administrations per day may be sufficient.
In one embodiment, the treatment regimen is 1 to 5 administrations per day (i.e., 1 to 5 administrations per day).
In one embodiment, the treatment regimen is 1 to 4 administrations per day (i.e., 1 to 4 administrations per day).
In one embodiment, the treatment regimen is 2 to 5 administrations per day (i.e., 2 to 5 administrations per day).
In one embodiment, the treatment regimen is 2 to 4 administrations per day (i.e., 2 to 4 administrations per day).
In one embodiment, the treatment regimen is 2 administrations per day (i.e., twice daily administration).
In one embodiment, the treatment regimen is 3 administrations per day (i.e., 3 administrations per day).
In one embodiment, the treatment regimen is 4 administrations per day (i.e., 4 administrations per day).
In one embodiment, the treatment regimen is an on-machine strain (PRN) (e.g., as needed, as the case arises, etc.).
Formulations
While isopropyl [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetate (also referred to herein as "AX-8" or "Gly-O-iPr") as described herein is potentially administered alone, it is preferably provided as a pharmaceutical formulation (e.g., composition, formulation, medicament) comprising the compound as described herein and one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, colorants, flavoring agents and sweeteners. The formulation may also contain other active agents, such as other therapeutic or prophylactic agents.
Pharmaceutical compositions and methods of preparing pharmaceutical compositions are described herein, including admixing a compound with one or more other pharmaceutically acceptable ingredients (e.g., carriers, diluents, excipients, etc.) well known to those skilled in the art. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dose) of the compound.
The term "pharmaceutically acceptable" as used herein relates to compounds, ingredients, materials, compositions, dosage forms, and the like which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject under consideration (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.
Suitable carriers, diluents, excipients, and the like can be found in standard pharmaceutical textbooks, for example, remington's Pharmaceutical Sciences, 18 th edition, mack Publishing Company, easton, pa.,1990, and Handbook of Pharmaceutical Excipients, 5 th edition, 2005.
The formulations may be prepared by any method well known in the pharmaceutical arts. Such methods include the step of associating the compound with a carrier constituting one or more adjunct ingredients. In general, formulations are prepared by uniformly and intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carriers, etc.), and then shaping the product if necessary.
Formulations for providing rapid or slow release, immediate, delayed, timed or sustained release, or combinations thereof may be prepared.
The formulations may suitably be in the form of liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, baits, mouthwashes, drops, tablets (including, for example, coated tablets), granules, powders, lozenges, pastilles, capsules (including, for example, hard and soft gelatin capsules), cachets, pills, ampoules, boluses, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, aerosols or aerosols.
In one embodiment, the compound is formulated as a spray.
In one embodiment, the compound is formulated as an aerosol.
In one embodiment, the compound is formulated as an aerosol.
The formulations may suitably be provided as patches, plasters, bandages, dressings and the like impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients including, for example, penetration, permeation and absorption enhancers. The formulation may also be suitably provided in the form of a depot or reservoir.
The compound may be dissolved, suspended in, or mixed with one or more other pharmaceutically acceptable ingredients.
Formulations suitable for oral administration (e.g., by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, baits, tablets, granules, powders, capsules, cachets, pills, ampoules and boluses.
In one embodiment, the compound is formulated as a tablet.
In one embodiment, the compounds are formulated as Orally Disintegrating Tablets (ODT), also known as orodispersible tablets, orally dissolving tablets, fast-dissolving tablets (rapid-dissolving tablet), fast-disintegrating tablets, or fast-dissolving tablets (fast-dissolving tablet). As considered herein, ODT is a pharmaceutical dosage form that disintegrates in saliva within a few minutes of topical application to the tongue surface. Preferably, the disintegration time is long enough to allow the compound to cover the mucosa. The main advantage of using ODT to deliver a compound is ease of administration (e.g., oral administration) and delivery to the site of action (e.g., locally rather than systemically).
Typical ODT consists essentially of an inert vehicle, diluent, or carrier. The agent (i.e., AX-8) is dispersed within such a carrier. ODT will dissolve when placed on the back of the tongue, releasing the drug agent, making it likely to contact the tissues of the lower oropharynx (LRO). Typical diluents, carriers or vehicles may be "polyols" interpreted to describe xylitol, mannitol, sorbitol, maltitol, isomalt, maltotriose, lactitol and beta-linked glucopyranose-sorbitol. Flavoring agents, such as sweeteners, aspartame, sucralose, or alitame, may be added to mask any taste. Typically, the mixture is granulated into a uniformly dispersed blend, dispersant, anti-caking agent, and/or lubricant may be added, and the mixture is then compressed to form the ODT. By way of example, the ODT used in the studies described herein comprises(Mannitol),CL-SF、SR 30D), sorbitol, anhydrous silica colloid, and magnesium stearate.
In one embodiment, the compound is formulated as ODT containing from about 0.5mg to about 50mg of the compound.
In one embodiment, the compound is formulated as ODT containing from about 1 to about 30mg of the compound.
In one embodiment, the compound is formulated as ODT containing from about 2 to about 20mg of the compound.
In one embodiment, the compound is formulated as ODT containing from about 2 to about 10mg of the compound.
In one embodiment, the compound is formulated as ODT containing about 5mg of the compound.
In one embodiment, the compound is formulated as ODT containing from about 50mg to about 250mg of the compound.
When the compound is a salt, ester, amide, prodrug, or the like, the amount applied is calculated based on the parent compound, and thus the actual weight to be used increases proportionally.
Formulations suitable for buccal administration include mouthwashes, lozenges, pastilles, patches, plasters, reservoirs and reservoirs. Lozenges generally comprise a flavoring base compound, typically sucrose and gum arabic or tragacanth. Pastilles typically comprise a compound in an inert base such as gelatin and glycerin, or sucrose and gum arabic. Mouthwashes typically comprise the compound in a suitable liquid carrier.
Formulations suitable for sublingual administration include tablets, troches, pastilles, capsules and pills.
Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), mouthwashes, sprays, aerosols, lozenges, pastilles, and patches, plasters, reservoirs and reservoirs.
Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions and oils, patches, plasters, bandages, dressings, reservoirs and reservoirs.
The tablets may be made in a conventional manner, for example, by compression or moulding, optionally together with one or more auxiliary ingredients. Compressed tablets may be prepared by compressing in a suitable machine a compound in a free-flowing form such as powder or granules, optionally mixed with one or more binders (e.g. povidone, gelatin, gum arabic, sorbitol, tragacanth, hydroxypropyl methylcellulose), fillers or diluents (e.g. lactose, microcrystalline cellulose, dibasic calcium phosphate), lubricants (e.g. magnesium stearate, talc, silica), disintegrants (e.g. sodium starch glycolate, crospovidone, sodium croscarmellose), surface-active or dispersing or wetting agents (e.g. sodium lauryl sulfate), preservatives (e.g. methyl parahydroxybenzoate, propyl parahydroxybenzoate, sorbic acid), flavouring agents and sweetening agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the compounds therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. The tablets may optionally be provided with a coating (e.g. to influence release), such as an enteric coating, to provide release in the part of the intestinal tract other than the stomach.
Ointments are generally prepared from the compounds with a paraffinic or water-miscible ointment base.
Creams are typically prepared from the compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base can include, for example, at least about 30% w/w of a polyol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, 1, 3-butanediol, mannitol, sorbitol, glycerin, and polyethylene glycol, and mixtures thereof. Topical formulations may desirably include a compound that enhances absorption or penetration of the compound through the skin or other affected area. Examples of such skin penetration enhancers include dimethylsulfoxide and related analogues.
Emulsions are typically prepared from a compound and an oil phase, which may optionally contain only emulsifiers (otherwise known as laxatives), or which may contain a mixture of at least one emulsifier with a fat or oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. And also preferably comprises oil and fat. In summary, emulsifiers with or without stabilizers constitute so-called emulsifying waxes, and the waxes together with oils and/or fats constitute so-called emulsifying ointment bases, which form the oily dispersed phase of the cream formulation.
Suitable emulsifiers and emulsion stabilizers include Tween 60, span 80, cetostearyl alcohol, myristyl alcohol, monostearin acid and sodium lauryl sulfate. The selection of the appropriate oil or fat for the formulation is based on achieving the desired cosmetic properties, as the solubility of the compound in most oils useful in pharmaceutical emulsion formulations can be very low. The cream should therefore preferably be a non-greasy, non-staining and washable product having a suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono-or dibasic alkyl esters may be used, such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or blends of branched chain esters known as Crodamol CAP, the last three being preferred esters. These substances may be used alone or in combination depending on the desired properties. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils may be used.
Formulations suitable for intranasal administration wherein the carrier is liquid include, for example, nasal sprays, nasal drops, or aerosols administered by nebulizer, including aqueous or oily solutions of the compounds.
Formulations suitable for intranasal administration in which the carrier is a solid include those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns, which are administered in a manner that is nasal inhalation, i.e., by rapid inhalation from a container of powder placed near the nose through a nasal passage.
Formulations suitable for pulmonary administration (e.g., by inhalation or insufflation therapy) include those presented from pressurized packages in the form of an aerosol spray with the aid of a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases.
In one embodiment, the compound is formulated as an aerosol spray.
Combination therapy
The term "treatment" includes combination therapies and therapies wherein two or more treatments or therapies are combined, e.g., sequentially or simultaneously. For example, the compounds [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester (also referred to herein as "AX-8" or "Gly-O-iPr") as described herein may also be used in combination therapies, for example in combination with other agents, such as one or more antitussives, expectorants, mucolytics, decongestants, nasal decongestants, first generation antihistamines, opioid analgesics, non-opioid analgesics, antipyretics, and the like, and combinations thereof.
The particular combination will be determined by the physician, who will use his general knowledge and dosing regimen known to the skilled practitioner to select a dose.
The agents (i.e., the compound, plus one or more other agents) may be administered simultaneously or sequentially, and may be administered in different dosage regimens and by different routes, alone. For example, when administered sequentially, the agents may be administered at closely spaced intervals (e.g., for a period of 5-10 minutes) or at longer intervals (e.g., at intervals of 1,2,3, 4 or more hours or even at longer periods of time when needed), the precise dosage regimen will be commensurate with the nature of the therapeutic agent.
The agents (i.e., the compound, plus one or more other agents) may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and provided together in kit form, optionally with their instructions for use.
Subject/patient
The subject/patient may be a mammal, placental mammal, pouchit mammal (e.g., kangaroo), rodent (e.g., guinea pig, hamster, rat, mouse), murine (e.g., mouse), lagomorph (e.g., rabbit), avian (e.g., bird), canine (e.g., dog), feline (e.g., cat), equine (e.g., horse), porcine (e.g., pig), ovine (e.g., sheep), bovine (e.g., cow), primate, ape (e.g., monkey or ape), monkey (e.g., marmoset, baboon), ape (e.g., gorilla, chimpanzee, gibbon), or human.
In a preferred embodiment, the subject/patient is a human.
Compounds configured for treatment of chronic cough
Also described herein is a compound comprising:
[ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof, the compound being configured for use in the treatment of chronic cough.
In one embodiment, [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for use in treating well-defined chronic cough.
In one embodiment, [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for use in treating chronic cough associated with or caused by a symptom of a disorder as a diagnosis.
In one embodiment, [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for use in treating chronic cough associated with or caused by a symptom of a cough associated disorder as a diagnosis.
In one embodiment, [ ((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is configured for use in treating chronic cough associated with or caused by asthma, eosinophilic bronchitis, post-nasal drip syndrome (PNDS), gastroesophageal reflux disease (GORD), bronchodilation Chronic Obstructive Pulmonary Disease (COPD), or Idiopathic Pulmonary Fibrosis (IPF).
In one embodiment, [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for use in treating Idiopathic Chronic Cough (ICC).
In one embodiment, [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for use in treating Refractory Chronic Cough (RCC).
In one embodiment, [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for use in treating Refractory Chronic Cough (RCC) that persists after evaluation and treatment of cough-related disorders.
In one embodiment, [ ((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for use in treating Refractory Chronic Cough (RCC) that persists following evaluation and treatment of asthma, eosinophilic bronchitis, post-nasal drip syndrome (PNDS), gastroesophageal reflux disease (GORD), bronchodilation Chronic Obstructive Pulmonary Disease (COPD) or Idiopathic Pulmonary Fibrosis (IPF).
In one embodiment, [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for use in treating chronic cough as, associated with or caused by allotussia symptoms.
In one embodiment, [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for use in treating chronic cough as, associated with or caused by hypertussia symptoms.
In one embodiment, [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for use in treating chronic cough associated with or caused by Cough Hypersensitivity Syndrome (CHS).
In one embodiment, [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for use in treating chronic cough associated with or caused by symptoms of Cough Hypersensitivity Reflex (CHR).
In one embodiment, [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for use in treating chronic cough associated with or caused by laryngeal paresthesia as a symptom.
In one embodiment, [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for use in treating chronic cough associated with or caused by Laryngeal Hypersensitivity Syndrome (LHS).
In one embodiment, [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for use in treating chronic cough that is a sensory nerve cough.
In one embodiment, [ ((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for use in treating chronic cough associated with or caused by peripheral sensitization, central sensitization (cough central), and/or cortical and/or subcortical maladaptability as a symptom.
In one embodiment, [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for use in treating chronic cough associated with or caused by vagal neuropathy as a symptom.
In one embodiment, [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for use in treating chronic cough associated with or caused by inflammation of the airways.
In one embodiment, [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for use in treating chronic cough associated with or caused by neurogenic inflammation and/or symptoms of neurogenic inflammation.
In one embodiment, wherein [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for treatment to:
Reducing cough frequency;
Reducing cough frequency per hour;
Reducing median cough frequency per hour;
reducing the average cough frequency per hour;
reducing the cough frequency per hour of wakefulness;
reducing the median awake cough frequency per hour;
reducing the average hourly cough frequency of wakefulness;
Reducing the cough frequency per hour of sleep;
reducing the median hourly cough frequency in sleep;
reducing average hourly cough frequency during sleep;
Reducing cough severity;
reducing cough with shortness and/or
Reducing throat irritation.
In one embodiment, [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for:
topical oral administration of the compound;
topical oral mucosal administration of the compound;
Topical buccal administration of the compounds;
topical sublingual administration of said compounds;
Topical intranasal administration of the compound, or
Topical transmucosal administration of the compounds;
in one embodiment, [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for:
a dose in the range of about 1 μg to about 5mg of compound per kilogram of body weight per day;
A dose in the range of about 5 μg to about 2mg of compound per kilogram of body weight per day;
A dose in the range of about 15 μg to about 0.7mg of compound per kilogram of body weight per day;
A dose in the range of about 30 μg to about 0.4mg of compound per kilogram of body weight per day, or
A dose in the range of about 70 μg to about 0.3mg of compound per kilogram of body weight per day.
In one embodiment, [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for:
a dose in the range of about 0.07mg to about 350mg of compound per day;
A dose in the range of about 0.35mg to about 140mg of compound per day;
a dose in the range of about 1mg to about 50mg of compound per day;
A dosage in the range of about 2mg to about 30mg of compound per day, or
A dose in the range of about 5mg to about 20mg of the compound per day.
In one embodiment, [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for:
treatment regimen of 1 to 5 administrations per day;
treatment regimen of 1 to 4 administrations per day;
treatment regimen of 2 to 5 administrations per day;
treatment regimen of 2 to 4 administrations per day;
treatment regimen of 2 administrations per day;
Treatment regimen of 3 times daily administration, or
Treatment regimen of 4 administrations per day.
In one embodiment, [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for use in an on-the-fly strain (PRN) treatment regimen.
In one embodiment, [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured to:
A tablet;
Orally Disintegrating Tablets (ODT);
A spray;
Aerosol or
An aerosol.
Method for manufacturing medicine
Also described herein is a method of manufacturing a medicament, the method comprising:
a medicament for the treatment of chronic cough is prepared comprising the compound [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof.
In one embodiment, preparing a medicament containing the compound includes preparing a medicament containing a compound for treating a well-defined chronic cough.
In one embodiment, preparing a medicament containing the compound includes preparing a medicament containing a compound for treating a symptom of, associated with, or caused by a condition as diagnosed.
In one embodiment, preparing a medicament containing the compound includes preparing a medicament containing a compound for treating a symptom of, associated with, or caused by a cough-related disorder as a diagnosis.
In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing a compound for treating chronic cough associated with or caused by asthma, eosinophilic bronchitis, post-nasal drip syndrome (PNDS), gastroesophageal reflux disease (GORD), bronchodilation Chronic Obstructive Pulmonary Disease (COPD) or Idiopathic Pulmonary Fibrosis (IPF).
In one embodiment, preparing a medicament containing the compound includes preparing a medicament containing a compound for treating Idiopathic Chronic Cough (ICC).
In one embodiment, preparing a medicament containing the compound includes preparing a medicament containing a compound for treating Refractory Chronic Cough (RCC).
In one embodiment, preparing a medicament containing the compound includes preparing a medicament containing a compound for treating Refractory Chronic Cough (RCC) that persists following evaluation and treatment of a cough-related disorder.
In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing a compound for treating Refractory Chronic Cough (RCC) that persists following evaluation and treatment of asthma, eosinophilic bronchitis, post-nasal drip syndrome (PNDS), gastroesophageal reflux disease (GORD), bronchodilation Chronic Obstructive Pulmonary Disease (COPD) or Idiopathic Pulmonary Fibrosis (IPF).
In one embodiment, preparing a medicament containing the compound includes preparing a medicament containing a compound for treating chronic cough associated with or caused by symptoms as allotussia.
In one embodiment, preparing a medicament containing the compound includes preparing a medicament containing a compound for treating chronic cough associated with or caused by symptoms as hypertussia.
In one embodiment, preparing a medicament containing the compound includes preparing a medicament containing a compound for treating chronic cough associated with or caused by symptoms of Cough Hypersensitivity Syndrome (CHS).
In one embodiment, preparing a medicament containing the compound includes preparing a medicament containing a compound for treating chronic cough associated with or caused by symptoms of hypersensitivity reflex (CHR) as cough.
In one embodiment, preparing a medicament containing the compound includes preparing a medicament containing a compound for treating chronic cough associated with or caused by symptoms of laryngeal paresthesia.
In one embodiment, preparing a medicament containing the compound includes preparing a medicament containing a compound for treating a symptom that is, associated with, or caused by, laryngeal Hypersensitivity Syndrome (LHS).
In one embodiment, preparing a medicament containing the compound includes preparing a medicament containing a compound for treating chronic cough that is a sensory nerve cough.
In one embodiment, preparing a medicament containing the compound includes preparing a medicament containing a compound for treating chronic cough associated with or caused by a symptom that is peripheral sensitization, central sensitization (cough central), and/or cortical and/or subcortical maladaptive plasticity.
In one embodiment, preparing a medicament containing the compound includes preparing a medicament containing a compound for treating chronic cough associated with or caused by symptoms of vagal neuropathy.
In one embodiment, preparing a medicament containing the compound includes preparing a medicament containing a compound for treating chronic cough associated with or caused by symptoms that are airway inflammation.
In one embodiment, preparing a medicament containing the compound includes preparing a medicament containing a compound for treating chronic cough associated with or caused by neurogenic inflammation and/or symptoms of neurogenic inflammation.
In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound to:
Reducing cough frequency;
Reducing cough frequency per hour;
Reducing median cough frequency per hour;
reducing the average cough frequency per hour;
reducing the cough frequency per hour of wakefulness;
reducing the median awake cough frequency per hour;
reducing the average hourly cough frequency of wakefulness;
Reducing the cough frequency per hour of sleep;
reducing the median hourly cough frequency in sleep;
reducing average hourly cough frequency during sleep;
Reducing cough severity;
reducing cough with shortness and/or
Reducing throat irritation.
In one embodiment, preparing a medicament containing the compound comprises preparing the medicament for:
topical oral administration of the compound;
topical oral mucosal administration of the compound;
Topical buccal administration of the compounds;
topical sublingual administration of said compounds;
Topical intranasal administration of the compound, or
Topical transmucosal administration of the compounds;
In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound as:
a dose in the range of about 1 μg to about 5mg of compound per kilogram of body weight per day;
A dose in the range of about 5 μg to about 2mg of compound per kilogram of body weight per day;
A dose in the range of about 15 μg to about 0.7mg of compound per kilogram of body weight per day;
A dose in the range of about 30 μg to about 0.4mg of compound per kilogram of body weight per day, or
A dose in the range of about 70 μg to about 0.3mg of compound per kilogram of body weight per day.
In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound as:
a dose in the range of about 0.07mg to about 350mg of compound per day;
A dose in the range of about 0.35mg to about 140mg of compound per day;
a dose in the range of about 1mg to about 50mg of compound per day;
A dosage in the range of about 2mg to about 30mg of compound per day, or
A dose in the range of about 5mg to about 20mg of the compound per day.
In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound as:
treatment regimen of 1 to 5 administrations per day;
treatment regimen of 1 to 4 administrations per day;
treatment regimen of 2 to 5 administrations per day;
treatment regimen of 2 to 4 administrations per day;
treatment regimen of 2 administrations per day;
Treatment regimen of 3 times daily administration, or
Treatment regimen of 4 administrations per day.
In one embodiment, preparing a drug containing the compound comprises preparing a drug containing the compound as an in-silico strain (PRN) treatment regimen.
In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound as:
A tablet;
Orally Disintegrating Tablets (ODT);
A spray;
Aerosol or
An aerosol.
Method for treating chronic cough
Also described herein is a method of treating chronic cough in a patient, the method comprising:
A therapeutically effective amount of the compound [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is administered to a patient in need of treatment of chronic cough.
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for a well-defined chronic cough.
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for symptoms of, associated with, or caused by a chronic cough as a diagnostic disorder.
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for symptoms of, associated with, or caused by a cough-related disorder as diagnosed.
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough associated with or caused by asthma, eosinophilic bronchitis, post-nasal drip syndrome (PNDS), gastroesophageal reflux disease (GORD), bronchodilation Chronic Obstructive Pulmonary Disease (COPD) or Idiopathic Pulmonary Fibrosis (IPF).
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for Idiopathic Chronic Cough (ICC).
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for Refractory Chronic Cough (RCC).
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for Refractory Chronic Cough (RCC) that persists following evaluation and treatment of the cough-related disorder.
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for Refractory Chronic Cough (RCC) that persists following evaluation and treatment for asthma, eosinophilic bronchitis, post-nasal drip syndrome (PNDS), gastroesophageal reflux disease (GORD), bronchodilation Chronic Obstructive Pulmonary Disease (COPD) or Idiopathic Pulmonary Fibrosis (IPF).
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough associated with or caused by symptoms as allotussia.
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough associated with or caused by symptoms as hypertussia.
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough associated with or caused by symptoms of Cough Hypersensitivity Syndrome (CHS).
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough associated with or caused by symptoms of Cough Hypersensitivity Reflex (CHR).
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough associated with or caused by symptoms of laryngeal paresthesia.
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough associated with or caused by symptoms of, as a Laryngeal Hypersensitivity Syndrome (LHS).
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough that is a sensory nerve cough.
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough associated with or caused by symptoms such as peripheral sensitization, central sensitization (cough central), and/or cortical and/or subcortical maladaptive plasticity.
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough associated with or caused by symptoms of vagal neuropathy.
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough associated with or caused by symptoms that are airway inflammation.
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough associated with, or caused by, as a symptom of neurogenic and/or neurogenic inflammation.
In one embodiment, the administering step comprises administering the compound to the patient to:
Reducing cough frequency;
Reducing cough frequency per hour;
Reducing median cough frequency per hour;
reducing the average cough frequency per hour;
reducing the cough frequency per hour of wakefulness;
reducing the median awake cough frequency per hour;
reducing the average hourly cough frequency of wakefulness;
Reducing the cough frequency per hour of sleep;
reducing the median hourly cough frequency in sleep;
reducing average hourly cough frequency during sleep;
Reducing cough severity;
reducing cough with shortness and/or
Reducing throat irritation.
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment by:
topical oral administration of the compound;
topical oral mucosal administration of the compound;
Topical buccal administration of the compounds;
topical sublingual administration of said compounds;
Topical intranasal administration of the compound, or
Topical transmucosal administration of the compounds;
in one embodiment, the administering step comprises administering the compound to a patient in need of treatment at the following doses:
a dose in the range of about 1 μg to about 5mg of compound per kilogram of body weight per day;
A dose in the range of about 5 μg to about 2mg of compound per kilogram of body weight per day;
A dose in the range of about 15 μg to about 0.7mg of compound per kilogram of body weight per day;
A dose in the range of about 30 μg to about 0.4mg of compound per kilogram of body weight per day, or
A dose in the range of about 70 μg to about 0.3mg of compound per kilogram of body weight per day.
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment at the following doses:
a dose in the range of about 0.07mg to about 350mg of compound per day;
A dose in the range of about 0.35mg to about 140mg of compound per day;
a dose in the range of about 1mg to about 50mg of compound per day;
A dosage in the range of about 2mg to about 30mg of compound per day, or
A dose in the range of about 5mg to about 20mg of the compound per day.
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment as follows:
treatment regimen of 1 to 5 administrations per day;
treatment regimen of 1 to 4 administrations per day;
treatment regimen of 2 to 5 administrations per day;
treatment regimen of 2 to 4 administrations per day;
treatment regimen of 2 administrations per day;
Treatment regimen of 3 times daily administration, or
Treatment regimen of 4 administrations per day.
In one embodiment, the administering step comprises administering the compound as an in-silico strain (PRN) treatment regimen to a patient in need of treatment.
In one embodiment, the administering step comprises administering the compound to a patient in need of treatment as:
A tablet;
Orally Disintegrating Tablets (ODT);
A spray;
Aerosol or
An aerosol.
Clinical trial 1
A first clinical trial using the compound [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester (also referred to herein as "AX-8" or "Gly-O-iPr") for the treatment of RCC was started, but ended prematurely. The basic details of the test are set forth in the following table.
At present, some details can be seen on the web:
https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-004803-30/GB
Clinical trial 2
A second clinical trial (open label stage IIa) using the compound [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester (also referred to herein as "AX-8" or "Gly-O-iPr") for the treatment of RCC was just completed. The basic details of the test are set forth in the following table.
At present, some details can be seen on the web:
https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-003108-27/GB
After completion of a second clinical trial (described in detail below), the compounds were found to have unexpected antitussive properties in RCC patients, thereby reducing the frequency of cough, throat irritation, cough with shortness and cough severity per hour of wakefulness. No adverse reactions associated with the compounds were observed.
As demonstrated by clinical trials, the 5mg dose of compound ameliorates cough in RCC patients by reducing the frequency of cough and also the Visual Analog Scale (VAS) score of all the cough characteristics evaluated (i.e., cough severity, cough jerk, throat irritation).
This is unexpected because MK-7264 (also known as AF-219 and gefarabine), a more advanced RCC drug currently being developed (stage 3 clinical trial beginning at 3 of 2018), is effective in reducing cough frequency, but does not work well in improving VAS scores in RCC patients (see, e.g., abdulqawi et al, 2015; smith et al, 2017a; smith et al, 2017b; smith et al, 2020). Cough severity was only significantly improved for doses of 50mg and 1200mg per day, with taste-related adverse events (i.e., dysgeusia, hypogeusia, or loss of taste) in 81% and 100% of patients, respectively. The cough with shortness was only shown to improve significantly at a dose of 1200mg per day. Phase 3 clinical trials (NCT 03449134 and NCT03449147,2020, which were still ongoing for 6 years) are studying MK-7264 at 15mg and 45mg doses.
AX-8 is the only compound that has been shown to reduce throat irritation in RCC patients.
Research objective
AX-8 bioavailability and safety have previously been addressed in phase 1 studies in healthy human subjects. However, up to now, AX-8 has not been studied in patients suffering from Chronic Cough (CC). The present study is a preliminary study of the efficacy, safety and tolerability of AX-8 for the treatment of Refractory Chronic Cough (RCC).
The main objective of the study was to evaluate the effectiveness of AX-8 (study drug) for treating RCC and related upper respiratory symptoms in reducing the frequency of awake coughing after one dose of treatment (orally disintegrating tablet (ODT) with 5mg AX-8, orally administered and dissolved on the tongue) compared to baseline, with the aim of planning a random control trial in the future.
A secondary objective of the study was to evaluate the duration of effectiveness in reducing the objective cough frequency per hour for AX-8 over a 24 hour monitoring period after 1 dose of treatment.
Another secondary objective of the study was to evaluate the effectiveness of AX-8 in (a) reducing cough severity as measured by the Visual Analog Scale (VAS), (b) reducing throat irritation and jerky cough (VAS), and (c) inducing a sensation of wetting the throat (VAS).
Another secondary objective of the study was to assess the safety and tolerability of AX-8 treatment in patients with RCC.
The exploratory goal (added to the study after the start) was to evaluate the Pharmacokinetic (PK) profile of AX-8.
Ethics, approval and locale
The study protocols, including all relevant documents, were reviewed and approved by the appropriate independent ethics committee. The study was performed according to the current version of the declaration of helsinki (declaration of Helsinki) (52 th WMA meeting, scotch Edinburgh, 10 2000). The study was conducted according to guidelines of the international conference on coordination (International Conference on Harmonisation, ICH) on Good Clinical Practice (GCP). The study was conducted as required by the drug and health care administration (MEDICINES AND HEALTHCARE products Regulatory Agency, MHRA). All patients provided written Informed Consent (ICF) for study participation prior to screening. The study was conducted at NIHR Manchester clinical institute (NIHR MANCHESTER CLINICAL RESEARCH FACILITY, CRF), manchester university NHS foundation letters (MANCHESTER UNIVERSITY NHS FOUNDATION TRUST, MFT), southmoor Rd, WYTHENSHAWE, MANCHESTER M23 LT, UK.
Study time
The study included five phases, with a total study period of about 4 weeks:
During screening, subjects received qualification and recruited.
On day 0 (visit 2; baseline visit), eligible subjects were monitored for cough for 24 hours and were assessed in the clinic for breathlessness cough (UTC), cough severity and throat irritation, respectively, using VAS over 4 hours and tracked in a home patient diary.
Subjects were asked to fasted overnight (at least 8 hours) prior to day 0 visit. Breakfast is provided at the unit at least 30 minutes before the subject installs the cough monitor. No food was taken within 4 hours after the cough monitor was installed. Liquid (including water) is not allowed until the cough monitor is installed, and is not allowed until 2 hours after the cough monitor is installed, and only a reasonable amount of water is allowed after 2 hours. After 4 hours, there was no food or liquid restriction.
On day 1 (visit 3; treatment visit), the eligible subjects received one 5mg AX-8 ODT. Cough monitoring was performed during 24 hours and different VASs for UTC, cough severity, throat irritation, throat wetting and taste perception were evaluated at the clinic using VAS within 4 hours after dosing and tracked at home with the patient diary.
Subjects were asked to fasted overnight (at least 8 hours) prior to day 1 visit. Breakfast was provided in the units at least 30 minutes before the subjects received the AX-8 dose. No food was allowed for 4 hours after dose administration. The liquid is not allowed until the dose is administered and is not allowed until 2 hours after administration (including water) after 2 hours, only a reasonable amount of water is allowed. After 4 hours, there was no food or liquid restriction.
The primary efficacy endpoint was assessed one day after treatment.
On day 2 (visit 4; follow-up visit), the cough monitor was removed and the patient diary was returned.
Between 7-14 days after day 1 (visit 5; study end visit), the study end visit was conducted.
Subjects who withdraw from the study after receiving the study medication and before completing the study ending visit were asked to complete an Early Withdrawal Visit (EWV), thereby conducting the same procedure as the study ending visit.
Recruitment of
Adult subjects with a history of RCC and associated upper respiratory symptoms (i.e., throat irritation/itching associated with cough episodes) were recruited into the study.
Inclusion criteria:
subjects must meet the following criteria to be recruited into the study:
Women and men between 18 and 80 years of age (inclusive).
Cough diagnosed as RCC or unknown cause for at least one year (see the british society of thoracic (British Thoracic Society, BTS) guidelines) and associated upper respiratory symptoms (throat or laryngeal irritation, itching, dryness or discomfort) for at least 8 weeks. The pattern of regularity of cough, as determined by the medical history, is the expected daily onset of cough that occurs throughout the day.
Chest radiographs or chest computer tomography over 5 years did not reveal any abnormalities that were considered by the main researchers and medical monitors to contribute significantly to chronic cough.
Cough severity VAS score > 40mm at screening visit.
At baseline visit, cough severity VAS score > 40mm.
All female subjects with fertility potential must conduct efficient contraception (i.e. pregnancy prevention method with failure rate of <1% per year) from the time of initial screening visit until 4 weeks after the last dose of study drug.
At baseline visit, body Mass Index (BMI) <33kg/m2.
Willing and able to follow all aspects of the scheme.
Provide written informed consent.
Exclusion criteria:
Subjects meeting any of the following criteria were not eligible to participate in the study:
previous treatment with AX-8.
Hypersensitivity or intolerance to AX-8 or other TRPM8 agonists (e.g. menthol, menthol compounds) or any excipient of AX-8 ODT.
Current smokers or individuals who have quitted smoking in the past 12 months or smokers who have quitted smoking more than >20 package-years.
One second forced expiratory volume (FEV 1)/Forced Vital Capacity (FVC) <60%.
Recent significant changes in pulmonary status within 4 weeks after the history of upper or lower respiratory tract infection or baseline visit.
History of cystic fibrosis.
There was a history of opioid use within 1 week after baseline visit if used to treat RCC. Opioid use is permitted if other indications require, provided that the subject receives a stable dose for at least 1 week prior to baseline visit and is still experiencing an unpleasant cough. The subjects must maintain a stable dose for the duration of the study until follow-up visit.
Synchronous treatment with disabled drug is required.
Treatment with biologic therapy within 8 weeks prior to baseline visit or within 5 half-lives, whichever is longer.
Treatment with any investigational therapy within 4 weeks prior to baseline visit.
Clinically significant liver dysfunction, defined as total bilirubin, alanine Aminotransferase (ALT) or aspartate Aminotransferase (AST) > 2-fold of the Upper Limit of Normal (ULN) during screening.
Clinically significant renal dysfunction, defined as estimated glomerular filtration rate (egffr) <60ml/min.
Any drug abuse test is positive (unless the subject's drug can explain this).
Complete treatment and non-metastatic basal cell carcinoma or cutaneous squamous cell carcinoma, except for a history of malignancy within 5 years prior to baseline visit.
History of major psychotic disorders (including major depressive disorder, bipolar disorder or schizophrenia), suicidal ideation or suicidal attempts.
Known active hepatitis infection.
A history of known Human Immunodeficiency Virus (HIV) infection.
There are any medical conditions or disabilities that the researcher believes may interfere with safety or efficacy assessment in the trial or jeopardize the safety of the subject, including clinically significant ECG abnormalities during screening, baseline or treatment visits.
Female subjects who are currently pregnant or lactating, or male subjects with pregnant or lactating partners.
Women with fertility potential who are unable or unwilling to conduct efficient contraception (preventing pregnancy).
Patients may withdraw from the study at any time without any explanation of the reasons. Researchers may also take patients out of the trial if they deem appropriate for safety or ethical reasons or if they are deemed to be adverse to the patient's health. The study protocol specifies that subjects must stop the study if the following events occur between recruitment and drug administration:
Female subject pregnant.
Subject decides to discontinue the study, or subject decides to withdraw study consent.
Researchers believe that any medical condition that may compromise the safety of the subject if the study medication is administered.
The investigator considers withdrawal to be of optimal benefit to the subject.
Eventually, no patient was withdrawn from the study and therefore EWV was not performed.
A total of 16 patients were screened. A total of 12 patients received treatment and completed the study. Efficacy and safety data were analyzed for 12 patients. The sample size of 10-15 patients compared to baseline measurements was considered sufficient to evaluate the antitussive effect of single dose treatment in terms of magnitude and duration.
Treatment of
The subject took a single Orally Disintegrating Tablet (ODT) containing 5mg AX-8 in the morning on the first day of the treatment period (day 1). The Investigational Medical Product (IMP) is allowed to dissolve on the tongue. The patient was observed for 5 minutes to ensure that the tablet dissolved on the tongue and was not swallowed.
ODT was administered on day 1 (visit 3; treatment visit) and before 10 am after the cough monitor was removed on day 0 (visit 2, baseline visit) (because RCC patients cough mainly during the day).
AX-8 ODT also contains(Mannitol),CL-SF、SR 30D), sorbitol, anhydrous silica colloid, and magnesium stearate. The IMP batch is number 17081402 (expiration date of 11 months 2018). ODT was kept in original packaging (i.e., HDPE bottles with polypropylene screw caps containing 50 sheets) until application. ODT is stored in a safe, temperature-controlled (no more than 30 ℃) controlled access location at the site of investigation.
The 5mg AX-8 dose selected for this study was based on the good safety and tolerability profile of AX-8 at 5mg ODT dose level as demonstrated by the phase 1 study in healthy volunteers. In the study, AX-8 was well tolerated in 12 subjects exposed to a single dose of AX-8 and had no significant Adverse Events (AE).
All study treatments were administered by either a study investigator or a designated staff member. To ensure medication responsibility, the investigator or designated agent maintains a ready record of the date and quantity of medication received, to whom to distribute, and accounts for any accidental or intentional destruction of supplies, with such detailed information being recorded on the medication responsibility table. All unused clinical supplies and drug liability charts were returned at the end of the study.
Previous and concurrent therapy
Synchronous therapy includes any therapy (including Over The Counter (OTC) drugs) that is used by the subject from the start of the treatment to the follow-up period. A record of all drugs used was kept for each subject throughout the study. The reported information includes descriptions of the type of drug, the treatment cycle, the dosing regimen, the route of administration, and the pharmaceutical indication.
Subjects using oral contraceptives, hormone replacement therapy, or other maintenance therapies that are not excluded from therapy may continue to use during the study. A record of all concurrent therapies was maintained for each subject.
The following therapies and products were excluded during the last 6 hours before and during all visit days:
Cough drops, over-the-counter cough syrups, chewing gums, caffeine, capsicum or products containing peppermint and/or menthol are consumed within the last 6 hours before and during the visit date.
From 1 week before baseline visit (day 0, visit 2) to the end of follow-up visit (day 2, visit 4), the following therapies were excluded:
Opioids (including codeine and morphine). Opioids (including codeine) are allowed if other indications require, provided that the subject receives a stable dose for at least one week prior to baseline visit (day 0) and is still experiencing an unpleasant cough. The subject must maintain a stable dose for the duration of the treatment period.
2 Weeks prior to baseline visit (day 0, visit 2) to the end of study visit (visit 5), the following cough therapies were excluded:
Dextromethorphan;
guaifenesin.
2 Weeks prior to baseline visit (day 0, visit 2) to the end of study visit (visit 5), the following therapies were excluded:
Pregabalin, gabapentin, thalidomide, or amitriptyline for the treatment of cough. Pregabalin, gabapentin, thalidomide, or amitriptyline is allowed if needed for other indications if the subject is receiving a stable dose and still experiencing an unpleasant cough. The subject must maintain a stable dose for the duration of the treatment period.
2 Weeks prior to baseline visit (day 0, visit 4) to the end of study visit (visit 5), the following therapies were excluded:
Systemic immunosuppression/immunomodulation therapies (including but not limited to PDE4 inhibitors, cyclosporines, mycophenolate mofetil, methotrexate, azathioprine, or phototherapy);
Any investigational therapy.
2 Weeks prior to baseline visit (day 0, visit 8) to the end of study visit (visit 5), the following therapies were excluded:
Biological therapy;
investigational biological therapy.
12 Weeks prior to baseline visit (day 0, visit 2) to the end of study visit (visit 5), the following therapies were excluded:
Treatment with ACE inhibitors.
From treatment visit (day 1, visit 3) to study end visit (visit 5), subjects were asked to take appropriate measures to minimize exposure to UV radiation (e.g., sunlight, sunbath).
Efficacy assessment
Objective cough frequency:
Objective cough frequency was measured using a custom digital recording device (VitaloJAK, vitalograph, ltd) as a 24-hour recording.
VitaloJAKTM is a semi-automatic 24 hour ambulatory cough monitoring system (Vitalograph; buckingham, england) that operates in a manner that fully replicates conventional practices. The 24 hour record is compressed using custom designed compression software, using an algorithm. VitaloJAKTM is a reliable, robust, and efficient tool for objective measurement of cough frequency. Importantly, it can reduce 24 hour recordings by up to 98% while retaining nearly 100% of the recorded cough sounds. It is worn like a Holter monitor, where a single sensor is fixed to the chest wall of the patient. An optional second channel through a conventional microphone (e.g. worn on the shirt of the patient) allows quality assurance through manual intervention. The device itself is attached to trousers, skirts, etc.
Cough severity:
Cough severity was scored according to the 100mm Visual Analog Scale (VAS) at the indicated time points. s requires the patient to indicate their assessment by marking (e.g., with a pen) the location along the 100mm line between the two extremes (e.g., "no cough" and "most severe cough").
Cough with shortness (UTC):
the cough with shortness was scored according to 100mm VAS at the indicated time points.
Throat irritation:
throat irritation was scored according to 100mm VAS at the indicated time points.
Throat wetting:
The throat is scored according to 100mm VAS at the indicated time points.
Change scale overall rating (GRCS):
subjects used GRCS to assess their overall status over a specified period (during 4 hours post dose; during 24 hours post dose). It consists of a 14-point scale, ranging from "very good" to "very bad".
Taste questionnaires:
Simple taste observation (qualitative) was completed. Freshness, basic taste (i.e., sweet, sour, bitter, and salty) and palatability were scored according to 100mm VAS at the indicated time points.
Security assessment
Safety assessments include monitoring and recording regimen-defined Adverse Events (AEs) and Severe Adverse Events (SAE), vital signs, physical examinations, clinical laboratory assessments, electrocardiography (ECG), and other regimen-specified tests that are considered critical to the safety assessment of study drugs.
Vital signs include measuring heart rate, sitting blood pressure, respiratory rate, and body temperature. Vital signs were assessed at designated time points and at unplanned study visits when clinical signs were present. The height and weight of the subject were also measured.
Physical examination was performed at the indicated time points and at the time of planned study visits with clinical indications, covering the major body systems (evaluation of ear, eye, nose and throat, head, neck, thyroid, nervous system, respiratory system, cardiovascular system, lymph nodes, abdomen, skin, musculoskeletal, nervous system).
Samples for hematology, chemistry, urinalysis, and serum pregnancy testing (as necessary) were collected at designated time points and at unplanned study visits at clinical indications, and analyzed at the local laboratory unless otherwise indicated.
Laboratory evaluations included the following:
Hematology: hematocrit, hemoglobin, red blood cell count, red blood cell index, platelets, white blood cell count, white blood cell classification (neutrophils, lymphocytes, monocytes, basophils, eosinophils).
Chemistry sodium, potassium, chlorine, bicarbonate, glucose, blood urea nitrogen, creatinine, gfr, calcium, phosphorus, magnesium, albumin, ALT, AST, alkaline phosphatase, total bilirubin, LDH, uric acid, total protein, and blood lipid.
Pregnancy test-all women with fertility potential were subjected to a local urine pregnancy test. Positive or ambiguous urine pregnancy test results were confirmed by serum pregnancy tests analyzed in the local laboratory. Serum pregnancy tests were performed in the screening visit (visit 1).
Urine analysis, pH, specific gravity, bilirubin, glucose, ketones, leukocytes, nitrite, blood, protein, urobilinogen, microscopic analysis.
Standard 12-lead ECG was performed at the indicated time points and at the time of an unscheduled study visit when there was a clinical indication.
Pulmonary function tests (FEV 1, FVC and FEV1/FVC ratios) were evaluated using a spirometer:
the one second forced expiratory volume (FEV 1) is the volume of air expired in one second using a spirometer.
Forced Vital Capacity (FVC) is the total amount of air that can be exhaled at one time.
FEV1 divided by FVC (FEV 1/FVC), which is the ratio of the total amount that can be exhaled in one second.
Activity and assessment timetable
Informed consent was obtained prior to any protocol-prescribed procedure, including termination of any excluded therapy.
Screening visit (visit 1):
screening evaluations were performed during the 14 day period prior to baseline visit. If any additional tracking of the results of any screening evaluation is required, the screening period may be extended to more than 14 days.
The following screening procedure was performed (not specified by the following order):
inclusion/exclusion criteria review.
Demographic data and medical history (including history of chronic cough, any drug history within 30 days prior to screening visit, and history of chronic cough treatment within 1 year prior to screening visit).
Physical examination.
Vital signs (including height and weight).
12 Lead ECG.
Spirometry.
Chest radiography or CT chest (if not done within the last 5 years).
Laboratory test:
serum pregnancy test for women with fertility potential.
Serology
Chemistry
Urine analysis.
Urine drug screening.
Cough severity VAS assessment.
Jerky cough VAS assessment.
Throat irritation VAS assessment.
Arrange for baseline visits.
Baseline visit (visit 2; day 0):
at baseline visit, the following procedures and evaluations (not specified by the following order) were performed:
inclusion/exclusion criteria review.
Update medical history.
Record all synchronized drug usage.
Vital signs.
12 Lead ECG.
Laboratory test:
urine pregnancy test for women with fertility potential.
Urine drug screening.
Subjects were provided with a VAS diary and instructed to complete the VAS assessment at home for +5 and +6 hours (see below).
Connect and activate a baseline visit cough monitor (preferably before 10 a.m.).
Cough severity VAS assessment:
prior to cough monitor installation:
-30 minutes.
After the cough monitor is installed:
+1, +2, +3, +4, +5, +6 hours.
Jerky cough VAS assessment:
prior to cough monitor installation:
-30 minutes.
After the cough monitor is installed:
+1, +2, +3, +4, +5, +6 hours.
Throat irritation VAS assessment:
prior to cough monitor installation:
-30 minutes.
After the cough monitor is installed:
+1, +2, +3, +4, +5, +6 hours.
Schedule treatment visit.
VAS assessment at +5 and +6 hours was done by the patient at home using a VAS diary. VAS evaluation at all other time points is completed at the unit. A time window of +/-5 minutes was allowed at all VAS time points.
Treatment visit (visit 3; day 1):
at least 24 hours after the baseline visit to the cough monitor on day 0, and preferably before 10 a.m., the clinic staff is engaged in the following activities (not specified by the following sequence):
Remove baseline visit cough monitor.
Update medical history.
Record all synchronized drug usage.
Inclusion/exclusion criteria review.
Patients were enrolled in the study if all inclusion and exclusion criteria were met.
Vital signs pre-dose and 4 hours post-dose.
12 Lead ECG (pre-dose).
Laboratory test:
urine abuse drug test.
Pharmacokinetic (PK) samples were collected.
Subjects were provided with a VAS diary and instructed to complete the VAS assessment at home for +5 and +6 hours (see below).
Before dosing, connect and activate the treatment visit cough monitor.
The dose of study drug administered (preferably before 10 a.m.).
Cough severity VAS assessment:
before dosage:
-30 minutes.
After the dosage:
+1, +2, +3, +4, +5, +6 hours.
Jerky cough VAS assessment:
before dosage:
-30 minutes.
After the dosage:
+1, +2, +3, +4, +5, +6 hours.
Throat irritation VAS assessment:
before dosage:
-30 minutes.
After the dosage:
+1, +2, +3, +4, +5, +6 hours.
Throat-wetting VAS assessment:
before dosage:
-30 minutes.
After the dosage:
+1, +2, +3, +4, +5, +6 hours.
GRCS evaluation 4 hours after dose.
Schedule a follow-up visit.
Once the investigator confirms that it is safe to do so, the subject may leave the unit after an assessment of 4 hours after dose completion.
VAS assessment at +5 and +6 hours was done by the patient at home using a VAS diary. VAS evaluation at all other time points is completed at the unit. A time window of +/-5 minutes was allowed at all VAS time points.
Follow-up visit (visit 4; day 2):
At least 24 hours after connecting the treatment visit cough monitor (day 1), the clinic staff performed the following activities (not specified by the following sequence):
remove treatment visit cough monitor.
Collect and check the integrity of the VAS diary.
Overall impression of day of treatment (24 hours):
Cough severity VAS assessment.
Jerky cough VAS assessment.
Throat irritation VAS assessment.
Throat-wetting VAS assessment.
GRCS evaluation.
Record all adverse events.
Record all synchronized drug usage.
Arrange for study end visit.
Study end visit (visit 5):
The following procedures and evaluations were performed at the clinic between day 7 and day 14. At this visit, the office staff underwent the following procedures and evaluations (not specified by the following sequence):
Cough severity VAS assessment.
Jerky cough VAS assessment.
Throat irritation VAS assessment.
GRCS evaluation.
Vital signs.
Body weight.
Physical examination.
12 Lead ECG.
Laboratory test:
Serology
Chemistry
Urine analysis.
Urine pregnancy test for women with fertility potential. Record all adverse events.
Record all synchronized drug usage.
The following table summarizes the timing of the various procedures and evaluations.
Annotation:
Endpoint (endpoint)
The primary efficacy endpoint was the change from baseline in the frequency of awake objective cough over 24 hours after 1 dose of treatment.
The key secondary efficacy endpoints are:
Changes in objective cough frequency per hour from baseline over a 24 hour monitoring period.
The proportion of subjects with a 24 hour cough frequency decrease of > 30% per hour.
The proportion of subjects with a reduction in awake cough frequency of > 30% per hour.
Changes in cough severity VAS from baseline.
Changes in cough-rapid VAS from baseline.
Changes in throat stimulation from baseline.
Throat-wetting VAS.
Change amount table overall rating (GRCS):
Efficacy variable
The 24 hour cough frequency (cough per hour) for a given visit is calculated as follows:
Cough frequency 24 hours= (total number of cough events during the monitoring period (24 hour interval)/24.
The awake cough frequency (cough per hour) is defined as follows:
awake cough frequency= (total number of cough events during monitoring period (24 hour interval) while the subject is awake)/(total duration (in hours) during monitoring period (24 hour interval) while the subject is awake).
The awake duration (hours) is defined as the time between waking and sleeping during a 24 hour monitoring period.
The cough data contains all cough events that occur during the 24 hour monitoring period and information about "sleep time" and "awake time". Any period of recording duration <4 hours is considered to be absent.
Generally, each 24-hour period consists of an awake monitoring period and a sleep monitoring period. If the subject has not awakened before the end of the recording period, it is assumed that the subject is sleeping for the remainder of the period. The epoch will then lack awake time and the remainder of the epoch will be considered under sleep monitoring period. For any period of absence of sleep time and awake time, the entire 24 hour period is considered to be in the awake monitoring period unless the period terminates recording prematurely.
At each collection day, the cough counts for the total 24 hour period, awake period and sleep period, actual cough monitoring duration (in hours), and cough per hour were derived, respectively.
The percent change in awake cough per hour is defined as follows:
percent change in awake cough frequency= [ (change in awake cough frequency from baseline x 100)/(baseline awake cough frequency) ].
The proportion of participants that reduced the frequency of awake cough by greater than or equal to 30% from baseline is the number of participants with less than or equal to-30% change in the frequency of awake cough divided by the total number of participants with available data.
In presenting the geometric mean of the 24 hour cough frequency (95% Confidence Interval (CI)), any observation of zero cough per hour was replaced with a cough rate of 0.1/hour to calculate the geometric mean.
Patient participation
16 Patients were on 2017, 12 months 12 and 2018 screening was performed between 5 months and 16 days of the year, and 11 patients completed the study end visit between day 1, 8 in 2018 and day 6, 11 in 2018.
The following table summarizes patient participation.
Patient demographics data
The following table summarizes the demographics of 12 patients.
4 Out of 12 patients had no data available.
Results-cough frequency
Raw hourly cough count data relative to dosing time is plotted as a complete analysis set and examined as an initial step.
Fig. 1 is a graph of median cough frequency (cough/hour) versus time after treatment (hours) for baseline (open circles) and treatment (filled circles).
The data show that treatment with a single dose of 5mg AX-8 produced an improvement in cough frequency per hour over a period of about 8 hours compared to baseline.
The table below shows summarized cough frequency data for each of five time windows (24 hours; awake; sleep; 8 hours; 4 hours).
Baseline and treatment data were compared for awake and sleep cough frequency using the Wilcoxon signed rank test due to the skewed nature of the data. The data are summarized in the following table.
Iqr=tetrad.
These data indicate a significant decrease in cough frequency (from 64.1 to 54.8; 14.5%) during awake hours. During sleep, the cough frequency is much lower and varies much more, and thus although the cough rate is reduced numerically (from 7.1 to 3.7; 48%) the difference may not be statistically significant for the sample size used (12 patients).
For 24 hour, 8 hour, and 4 hour cough frequencies, the baseline and treatment data were compared using a General Estimation Equation (GEE) model. Prior to analysis, these cough count data were subjected to a natural log (Ln) conversion to normalize the distribution of the data. Since some individuals had a cough count of zero per hour, 0.1 was added to all values prior to conversion. The data are summarized in the following table.
SE = standard error. CI = confidence interval.
These data demonstrate a significant improvement in cough frequency per hour for treatment over baseline during the 4 hour period and 8 hour period. It appears that the effect may be diminished after 8 hours and thus the cough frequency is not significantly reduced when analyzed throughout the 24 hour recording period.
The data for individual subjects for each of the five time windows (awake; sleep; 24 hours; 8 hours; 4 hours) are shown in fig. 2-6.
Fig. 2 is a graph showing the average awake cough frequency (cough/hour) for 12 individual patients for both baseline and treatment.
Fig. 3 is a graph showing the average sleep cough frequency (cough/hour) for 12 individual patients for both baseline and treatment.
Fig. 4 is a graph showing the average cough frequency (cough/hr) of 12 individual patients during the 24 hour post-treatment and equivalent baseline period.
(The values reported in FIGS. 2, 3, and 4 were subsequently determined to be "average" values, rather than the "median" values originally reported.)
Fig. 5 is a graph showing median cough frequency (cough/hr) for 12 individual patients during 8 hours post-treatment and equivalent baseline periods.
Fig. 6 is a graph showing median cough frequency (cough/hr) for 12 individual patients during the 4 hour post-treatment and equivalent baseline period.
Data demonstrates:
4/12 subjects (33.3%) experienced a decrease in the frequency of awake coughing per hour of ≡30%.
4/12 Subjects (33.3%) experienced a reduction in cough frequency of > 30% per hour at 24 hours.
5/12 Subjects (41.7%) experienced a reduction in cough frequency of > 30% per hour at 4 hours.
7/12 Subjects (58.3%) experienced a reduction in cough frequency of > 30% per hour at 8 hours.
Results-cough severity and related sensations
At various time points, patients were asked to report cough severity, throat irritation, cough with shortness, and throat wetting using the 100mm Visual Analog Scale (VAS).
The data for the screening visit and the study end visit and the data for the follow-up visit (evaluation of the total ≡24 hour period after dosing) are shown in the table below.
(A) These values are then determined to be "median" values, rather than the "average" values reported initially.
(B) It was then determined that the originally reported value (shown in brackets) was incorrectly calculated.
The data indicated a significant reduction in post-treatment cough severity (from 61.5 at screening to 47.0 at follow-up, then back to 64.0 at the end of the study). Similarly, the data indicated a significant decrease in throat irritation after treatment (from 55.0 at screening to 9.0 at follow-up, then back to 47.0 at the end of the study). Finally, the data indicated that there was also a decrease in post-treatment cough (from 51.5 at screening, to 46.0 at follow-up, then back to 57.0 at the end of the study).
Figures 7-10 show data for cough severity, throat irritation, cough with shortness, and throat wetting, per hour, immediately prior to treatment and within 6 hours after treatment. (throat wetting was assessed every half hour for the first 3 hours after treatment.)
Fig. 7 is a graph of median cough severity (VAS) (mm) versus time after treatment (hours) for baseline (open inverted triangle) and treatment (filled inverted triangle).
Fig. 8 is a graph of median cough with shortness (VAS) (mm) versus time after treatment (hours) for baseline (open diamonds) and treatment (filled diamonds).
Fig. 9 is a plot of median throat stimulation (VAS) (mm) versus time (hours) after treatment for baseline (open squares) and treatment (filled squares).
Fig. 10 is a graph (solid upper triangle) of median throat wetting (VAS) (mm) versus time after treatment (hours).
Cough severity data indicated that in the 6 hour monitoring, the patient felt a sustained relief from the first hour (see fig. 7). The cough data also indicated a sustained improvement from the first hour over the 6 hour period of monitoring, with a clear maximum occurring at about 3 hours (see fig. 8). Throat irritation data also indicated improvements from the first hour that persisted in the 6 hour monitoring, however, the baseline for treatment was lower compared to the baseline day (see figure 9). The throat-wetting data showed only an increase at 30 minutes and little difference was perceived by 1 hour and after (see fig. 10).
Fig. 11 is a composite graph showing median rapid cough (VAS) (mm) (filled diamond), throat irritation (VAS) (mm) (filled square) and throat wetting (VAS) (mm) (filled upper triangle) on the left side and median cough frequency (cough/hour) versus time (hours) after treatment for baseline (open circles) and treatment (filled circles) on the right side.
When the data for throat irritation, cough and throat wetting overlap with the data for cough frequency (baseline and treatment) (see fig. 11), the temporal relationship between sensation and possible antitussive effects can be assessed. The data indicate that throat sensation precedes (and has previously resolved) subsequent improvement of throat irritation and acute cough. This suggests that the primary mechanism of action is not antagonistic. This also suggests that the observed effect (e.g., reduced cough frequency) is not due solely to the placebo effect, as the patient will experience immediate effect (i.e., throat-wetting) regression. The data also indicate that improvement in throat irritation and cough with shortness may be a precursor to improved cough frequency.
Results-Total rating of Change Meter (GRCS)
The overall rating (GRCS) of the change scales assessment data obtained 4 hours after treatment and 24 hours after treatment are summarized in the following table.
* One patient provided GRCS at 4 hours instead of 24 hours.
Conclusion of efficacy
Based on the data, the following conclusions can be drawn:
In this uncontrolled preliminary study, AX-8 significantly reduced the cough frequency during awake hours in Refractory Chronic Cough (RCC) patients compared to baseline (no treatment).
The effect appears to be most pronounced within 4-8 hours.
The effect is accompanied by a reduction in the severity of cough reported by the patient.
The effect is also accompanied by a reduction in throat irritation and cough shortness reported by the patient, both of which are sensations associated with cough in refractory chronic cough patients.
Throat wetting is only a transient experience and appears to precede improvements in cough frequency, cough severity and sensation associated with cough.
Additional investigation of mode of action
The mode of action of the compound [ ((1 r,2s,5 r) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino ] -acetic acid isopropyl ester (also referred to herein as "AX-8" or "Gly-O-iPr") in the treatment of Chronic Cough (CC), including, for example, refractory Chronic Cough (RCC) and Idiopathic Chronic Cough (ICC), is not fully understood, in part because the mechanism of CC (including, for example, RCC, ICC) is still poorly understood.
The compounds are agonists of the transient receptor potential melanostatin 8 (TRPM 8) cation channel, also known as cold and menthol receptor 1 (CMR 1).
However, evidence suggests that a unique combination of several properties of the compounds (e.g., local mode of action; high potency; high selectivity over TRPM 8; high efficacy against specific target tissues, e.g., against non-keratinized stratified epithelium-NKSE) yields unexpected efficacy in treating CC (including, e.g., RCC, ICC) as compared to other TRPM8 agonists and known antitussives.
Menthol is a typical agonist of TRPM8 ion channels. Menthol has been used for several decades for anti-cough Over The Counter (OTC) treatment. Menthol efficacy is recognised in acute cough, although some studies have failed to demonstrate significant antitussive effects (see, e.g. Kenia et al, 2008; haidl et al, 2001). Menthol has never been shown to improve chronic cough in CC patients, and conversely, it has been shown to improve induced cough (see, e.g., MILLQVIST et al, 2013). In addition, menthol can induce adverse reactions such as airway irritation, dyspnea, increased mucus production with reduced cilia activity, resulting in mucus stasis, chest distress, and potential respiratory failure, mainly upon inhalation by children, and acid reflux and heartburn upon oral administration (see, e.g., gavliakova et al, 2013).
The antitussive effect of menthol (see, e.g., maher et al, 2014) and some of its side effects may be due to its activity on targets other than TRPM 8. Several tens of publications have demonstrated that menthol can significantly affect many different classes of channels and functional properties of receptors, including TRP channels (TRPA 1, TRPV3; see, e.g., takaishi et al, 2016), other ligand-gated channels (e.g., GABAa, glycine, nACh, and 5-HT3 receptors), G protein-coupled receptors (e.g., kappa-opioid receptors; see, e.g., galeotti et al, 2002), and voltage-gated channels (e.g., voltage-gated sodium and calcium channels) (see Oz et al, 2017 for reviews).
Camphor and eucalyptol, each of which is an agonist of TRPM8 ion channels, are also used for cold and cough Over The Counter (OTC) treatment. Like menthol, they are less selective and can be potentially adversely affected (see, e.g., gavliakova et al, 2013).
Plate reader using fluorescence imagingDetermination (study by ChanTest/CHARLES RIVER) AX-8 efficacy was assessed. The in vivo effects of cloned human TRPM8 channels expressed in CHO cells were evaluated using a Fluo-8 calcium kit and a fluorescence imaging reader (FLIPRTETRATM) instrument. The change in fluorescence intensity reflecting the calcium flux through hTRPM was measured and the area under signal (area under curve, AUC) was calculated and expressed in relative light units. The change caused by the vehicle (HEPES buffered saline, HB-PS) was subtracted. Half maximal response concentration (EC50) was calculated, indicating that AX-8 was almost 6 times as potent as TRPM8 agonist as menthol (EC50 = 0.39 μm and 2.29 μm, n = 8, respectively; see fig. 12 and 13).
Similarly, use is made ofThe calcium assay (at 100. Mu.M, i.e., a concentration exceeding 10 times the maximum response; see FIG. 12) evaluates the selectivity towards hTRPA (expressed in CHO) and hTRPV1 (expressed in HEK-293). Indeed, menthol has been shown to have bimodal activity on TRPA1 (see, e.g., KARASHIMA et al, 2007) and inhibit TRPV1 (see, e.g., takaishi et al, 2016), both of which are associated with TRPM8 and are expressed in nociceptors (sensory neurons that respond to noxious stimuli). For agonist effect assessment, the effect of AX-8 was assessed in the absence of positive control agonist. The maximum signal elicited in the presence of the corresponding agonist (300. Mu.M mustard for TRPA 1; 3. Mu.M capsaicin for TRPV 1) was set to 100% activation, and the signal in the presence of the vehicle control (HB-PS) was set to 0% activation. For antagonist effect assessment, the channels were activated with the corresponding positive control agonist (100. Mu.M mustard oil for TRPA 1; 0.1. Mu.M capsaicin for TRPV 1). The effect of AX-8 inhibition signal was examined after agonist stimulation and compared to the corresponding positive control antagonist (3. Mu.M ruthenium red). For each channel, the signal elicited in the presence of the corresponding positive control agonist was set to 100 (0% inhibition), and the signal elicited in the presence of the corresponding positive control antagonist was set to 0 (100% inhibition). The assay indicated that AX-8 was selective for TRPM8 channels, and no agonistic or antagonistic interactions with TRPV1 and TRPA1 channels were observed (see fig. 14 for agonistic effects).
FIG. 12 is a schematic representation of a process as performed byA graph of the activation of human TRPM8 by the obtained AX-8 was determined. Dose response curves are expressed as calcium signal (calculated from area under the curve-AUC, mean ± sem, n=8) versus AX-8 concentration (μm, logarithmic scale) expressed in relative light units. The half maximal response concentration (EC50) of AX-8 was found to be 0.39. Mu.M.
FIG. 13 is a schematic representation of a process as performed byA graph of the activation of human TRPM8 by the menthol obtained was determined. Dose response curves are expressed as calcium signal (calculated from area under the curve-AUC, mean ± sem, n=8) versus menthol concentration (μm, logarithmic scale) expressed in relative light units. The half maximal response concentration (EC50) of menthol was found to be 2.29. Mu.M.
FIG. 14 is a graph showing comparative activation of human TRPA1 and human TRPV1 by AX-8 and its reference agonist. For hTRPA1, the dose response curves for mustard oil (reference TRPA1 agonist) and AX-8 are expressed as a percentage of the maximum response of mustard oil (mean ± SD, n=4) to the concentration of agonist (μm, logarithmic scale). The data indicate that AX-8 has no significant agonistic activity on hTRPA <1 > at a concentration of < 100. Mu.M. For htpv 1, the dose response curves for capsaicin (reference TRPV1 agonist) and AX-8 are expressed as a percentage of capsaicin maximum response (mean ± SD, n=4) versus agonist concentration (μm, logarithmic scale). The data indicate that AX-8 has no agonistic activity on hTRPV 1at a concentration of less than or equal to 100. Mu.M.
In addition, an off-target pharmacological study (safety screening 87 by Eurofins Pharma Discovery Services (SAFETYSCREEN, assay) was performed. This assay package consisted of 87 primary molecular targets, including 13 enzymes and 74 binding assays, representing potential safety issues. No significant response was observed at 100 μm AX-8, confirming the high selectivity of AX-8 over its effective concentration range.
The vagus nerve is the primary afferent pathway of the cough reflex circuit. Thus, the ability of AX-8 to inhibit capsaicin-induced depolarization on the isolated guinea pig vagus nerve and dependence on TRPM8 was assessed. The tissue is measured using an O2/CO2 aeration, grease gap recording system as previously described (see, e.g., et al, 2009). Briefly, after tissue stabilization, it is exposed to challenge (capsaicin, 1 μm, TRPV1 agonist for 2 min) and then washed. This operation is then repeated to confirm the base response. After washing, the tissue was incubated with vehicle or AX-8 (10 nM-1 mM) for 10 min. After this, the tissue was re-stimulated with capsaicin (in the presence of vehicle or AX-8). After the wash phase, the tissue was stimulated with capsaicin to demonstrate tissue viability and response recovery.
In the case of TRPM8 antagonist PF-05105679 (PF, 10 μm), after two reproducible responses to capsaicin, the nerves were incubated with TRPM8 antagonist or vehicle (0.1% dmso) for 10 minutes and then with AX-8 or vehicle for 10 minutes. The nerves were then re-stimulated with capsaicin in the presence of PF/vehicle and AX-8/vehicle, and the percentage of inhibition of the original response was calculated. After the wash period, the nerves were then re-stimulated with capsaicin to determine viability. The depolarization level was recorded at each stage. Data are recorded as the percent inhibition (caused by vehicle or test compound) of the actual depolarization level and the average of the initial control recordings.
This study showed that AX-8 inhibited capsaicin-induced responses in guinea pig vagal explants by up to 80% in a dose-dependent manner (see fig. 15, n=3, i.e., tissue from 3 different guinea pigs). This inhibition was suppressed by pre-application of TRPM8 antagonist PF-05105679, confirming that the effect of AX-8 is mediated by the selective activation of TRPM8 (see fig. 16, n=4). In contrast, menthol inhibits capsaicin-induced responses in guinea pig vagal explants in a TRPM 8-independent manner (see, e.g., maher et al, 2014).
FIG. 15 is a bar graph showing inhibition (%) of AX-8 response to capsaicin induction versus AX-8 concentration (. Mu.M) in guinea pig vagal explants. AX-8 (n=3) blocked capsaicin-induced responses in guinea pig vagus nerves in a dose-dependent manner.
FIG. 16 is a bar graph showing inhibition (%) of AX-8 (1. Mu.M) response to capsaicin induction in guinea pig vagal explants in the presence or absence of the selective TRPM8 antagonist PF-05105679 (PF, 10. Mu.M). Two consecutive 10 min incubations were performed under four different conditions, vehicle (0.1% dmso)/vehicle, PF/vehicle, vehicle/AX-8 and PF/AX-8 (n=4). The selective TRPM8 inhibitor PF-05105679 can block the inhibition of the response induced by stimulatory capsaicin in guinea pig vagal explants, demonstrating that the effect of AX-8 is TRPM8 dependent.
The antitussive effect of AX-8 was evaluated in a standardized guinea pig cough model (see, e.g., brozmanova et al 2012; dong et al 2016). Guinea pigs were placed in the plethysmographic chamber and exposed to nebulized capsaicin solution (0.1 mM) for 10 minutes to induce cough. The cough frequency is detected as a momentary change in the indoor airflow and a signal is recorded by a pressure sensor and computer. In addition, the audio amplification count is also recorded electronically. Coughs during 10 minutes of exposure were counted. The experiment was monitored visually by the investigator. A5 mg/mL AX-8 solution was prepared by dissolving AX-8 at 200mg/mL in absolute ethanol, followed by dilution in a solution of 4mg/mL sweet potato flour in saline (i.e., vehicle).
The baseline frequency of coughing in response to exposure to capsaicin mist was recorded for animals of the control (vehicle only) and treatment (AX-8) groups (n=10 animals per group). After 7 days, the animals were anesthetized with diethyl ether and the tips of the micro-nebulizer syringes were placed in the mouth using a small animal laryngoscope. Vehicle or AX-8 was administered into the oropharyngeal region (n=10 animals per group) in an amount of 75 μl per animal. This corresponds to a dose of 0.375mg per animal. Ten minutes after administration, guinea pigs were exposed to capsaicin mist and the number of coughs was recorded.
The AX-8 solution significantly inhibited capsaicin-induced cough (p <0.01, see fig. 17).
FIG. 17 is a bar graph showing the effect of AX-8 on capsaicin-induced cough in awake guinea pigs. Vehicle did not significantly affect capsaicin-induced cough in guinea pigs (baseline (V) =24.8±2.1 coughs/10 min versus vehicle=21.4±2.4 coughs/10 min). Spraying 75 μl of 5mg/mL AX-8 solution (i.e. 0.375 mg/animal) in the oropharyngeal region inhibited capsaicin-induced cough in guinea pigs from 25.0±2.0/10 min cough (baseline (T)) to 9.0±2.0/10 min cough (p < 0.01). The number of animals per group was 10 (n=10).
Similarly, the putative site of action of the research medical product (IMP) containing AX-8 for the treatment of CC (including, e.g., RCC, ICC) is on the upper respiratory and digestive tract, oropharyngeal mucosal surface-posterior to the buccal cavity-and the esophagus. Thus, the expected mode of action of AX-8 as an antitussive is through activation of the sensory nerve endings expressing TRPM8 in this region. The coated mucosa of the mouth and esophagus is a typical example of non-keratinized stratified squamous epithelium (NKSE). AX-8 is a potent, long-acting and selective coolant for non-keratinized epithelial tissue (as well as permeable keratinized tissue such as eyelid skin) as compared to keratinized epithelial tissue and as compared to other related coolants (e.g., gly-OEt also known as WS-5, see, e.g., wei et al 2012). These unique properties not only distinguish AX-8 from other TRPM8 agonists, but are likely to also act synergistically to produce the unexpected efficacy of AX-8 as a potent antitussive for the treatment of CC (including, e.g., RCC, ICC).
Reference material
Numerous publications are cited herein to more fully describe and disclose the present invention and the state of the art to which the present invention pertains. The following provides a complete citation of these publications.
Each of these publications is incorporated by reference in its entirety into this disclosure to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.
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